Schizophrenia is a debilitating mental disorder characterized by psychosis, negative symptoms and neurocognitive deficits (Jablensky et al., (1992) Psychol. Med. Monogr Suppl. 20:1-97). Theories of the pathophysiology underlying schizophrenia have centered on neurotransmitters and their receptors and therapeutic drug development has largely targeted dopamine, serotonin and glutamate systems (Javitt D C, Laruelle M. Neurochemical theories. In: Lieberman J A, Stroup T S, Perkins D O, eds. Textbook of Schizophrenia. Washington D.C.: American Psychiatric Publishing; 2006:85-116; Meltzer, 9187) Schizophr. Bull. 13:77-111; Scolnick, (2006) Biol. Psychiatry 59:1039-45). While such therapies have proven effective in short-term trials, the vast majority of individuals discontinue treatment over time for lack of effectiveness or development of side effects and not all patients respond similarly to these medications (Strauss et al., (1977) Arch. Gen. Psychiatry 34:159-63; Kane et al., (1993) Schizophr. Bull. 19:287-302; Carpenter et al., (1994) N. Engl. J. Med. 330:681-690; Lieberman et al., (2005) N. Engl. J. Med. 353:1209-23).
In addition, recent studies have highlighted a growing concern over the potential for antipsychotic drugs, especially clozapine and olanzapine, to cause metabolic adverse effects such as weight gain, hyperglycemia, and hypertriglyceridemia (American Diabetes Association APA, American Association of Clinical Endocrinologists, North American Association for the Study of Obesity. Consensus Development Conference on Antipsychotic Drugs and Obesity and Diabetes, (2004) J. Clin. Psychiatry 65:267-72). For example, a 26-week randomized trial of 317 schizophrenic patients found that patients randomized to olanzapine were more likely to develop weight gain and total cholesterol/triglyceride elevations than those randomized to aripiprazole (McQuade et al., (2004) J. Clin. Psychiatry 65 Suppl. 18:47-56). However, to date no study has done comprehensive analyses of global lipid effects of various atypical antipsychotics.
The development of antipsychotic drugs in the 1950s, and the pioneering work of Arvid Carlsson, led to the subsequent advancement of the dopamine hypothesis of schizophrenia. The elucidation of dopamine pathways in the CNS, and the subsequent identification of dopamine antagonism as the common mechanism of action for typical antipsychotic medications, permitted the development of dozens of active molecules for the treatment of schizophrenia. The strength of the dopamine hypothesis is that it explains why, to date, no effective antipsychotic medication has been developed which does not, in some way, modulate dopamine neurotransmission. The limitations are clear, and relate to the large body of evidence that implicates other developmental processes and receptor pathways in the pathogenesis and manifestations of schizophrenia including other receptors such as serotonin and glutamate.
The synthesis of antipsychotic medications resulted in dramatic improvements for many sufferers of schizophrenia, and allowed many to resume life in the community. While the conventional antipsychotic drugs, such as the phenothiazines and haloperidol, are often effective in the treatment of the positive symptoms of schizophrenia, they offer little or no control of negative symptoms, and do not usually improve the cognitive deficits associated with schizophrenia, and may even exacerbate them. The conventional antipsychotic drugs are all potent dopamine D2 antagonists, and suffer from a very narrow therapeutic index whereby doses sufficient to control symptoms often result in the development of adverse reactions such as extrapyramidal effects (EPS) (e.g., parkinsonism), and a 4-5% annual incidence of tardive dyskinesia.
The newer generation of antipsychotics, often referred to as atypicals, offer two major advantages. Firstly, they are characterized by a much broader separation between the doses required for therapeutic response and those that induce extrapyramidal side effects. In addition, and to varying extents, the new drugs can improve the negative as well as the positive symptoms of schizophrenia. They also appear to offer some improvement in schizophrenia-associated cognitive deficits. Both the expanded therapeutic index and the lowered tendency to induce EPS are thought to depend on the fact that the atypicals are weaker antagonists of dopamine D2 receptors than typicals, but are potent antagonists of serotonin 5-HT2 receptors.
Despite the clear benefits of atypicals, however, many patients continue to suffer to some degree from a lack of control of negative symptoms, and from cognitive impairments. In addition, the atypical antipsychotics may cause serious metabolic side effects such as weight gain, hyperlipidemia and glycemic complications. Some of the atypicals, particularly risperidone, also carry a risk of EPS and hyperprolactinemia, albeit usually lower than for conventional antipsychotics. In addition, some patients, classified as “treatment resistant,” do not respond to any existing antipsychotic drugs. This population has been estimated to be as high as 30% of schizophrenia patients, and represents a major unmet clinical need.
While schizophrenia is associated with psychosis, emotional and cognitive dysfunction, one important clinical feature of schizophrenia is the greater risk than other members of society for developing obesity and metabolic disorders such as type 2 diabetes mellitus (DM) and the metabolic syndrome. This high prevalence of metabolic dysfunction is thought to be related to many factors including possible inherent vulnerability, inactive lifestyle, poor dietary choices, and side effects of psychotropic medications. Diabetes mellitus in particular has received significant attention in the schizophrenia literature over the past 5 years for several reasons: a) recent data confirming that DM is twice as prevalent among schizophrenia cohorts than in the general population; b) the concern about glucose intolerance, DM and diabetic ketoacidosis associated with atypical antipsychotic therapy culminating in FDA warnings and the recent American Diabetes Association/American Psychiatric Association (ADA/APA) Consensus paper on this topic (American Diabetes Association, A.P.A., American Association of Clinical Endocrinologists, North American Association for the Study of Obesity, Consensus Development Conference on Antipsychotic Drugs and Obesity and Diabetes, J. Clin. Psychiatry 65: 267-272 (2004); and c) changes in the third revision of the National Cholesterol Education Program's Adult Treatment Protocol (ATPIII) which elevated DM to a disorder considered equivalent in 10-year risk for a major cardiovascular event to established coronary heart disease (CHD).
It is hypothesized that a predilection towards abdominal or visceral adiposity places schizophrenia patients at risk for development of the metabolic syndrome, and eventually for type 2 DM through the correlation with decreased insulin sensitivity.
There may be several factors underlying the observation that patients with schizophrenia are at risk for the metabolic syndrome. Aside from a predisposition towards central obesity, environmental factors such as diet, inactivity, and the contributions of atypical antipsychotics play a significant role. The ADA/APA Consensus paper recognized that certain atypical antipsychotics are associated with greater metabolic dysfunction than others, including weight gain, hypertriglyceridemia, and risk of new onset DM or hyperglycemia. Prospective data on weight gain show mean increases during the first year of therapy of 11.7-13.9 lbs for clozapine, and 15.0-26.0 lbs for olanzapine, while risperidone and quetiapine reported mean gains of 4.4-5.1 lbs and 6.1-12.3 lbs respectively, and ziprasidone and aripiprazole<2 lbs. Multiple sources of data also reveal that treatment with clozapine or olanzapine is associated with increases in serum triglycerides over the first year of treatment ranging from 50 to over 100 mg/dl with serum levels over 7000 mg/dl reported, while aripiprazole and ziprasidone appear lipid-neutral, and discrepant data exist on risperidone and quetiapine. Although patients with schizophrenia have a vulnerability towards DM which places them at risk for this outcome even with metabolically neutral agents such as haloperidol, the accumulated body of evidence points towards clozapine and olanzapine as agents associated with higher risk, while ziprasidone and aripiprazole appear to have minimal effects on serum glucose.